Stereochemistry plays an important role in biological functions and drug design. In many instances, one stereoisomer of a compound may have positive effects on the human body while another stereoisomer may not work at all or may even be toxic. In a well-known example, one stereoisomer of ibuprofen works well as a pain killer while the other stereoisomer is completely ineffective at treating pain. In another well-known example, the drug thalidomide was widely used to suppress morning sickness in pregnant women in the 1950s. At the time, the drug was prescribed as a racemic mixture (i.e. a 50:50 mixture of the two stereoisomers). In this case, while one stereoisomer worked on controlling morning sickness, the other stereoisomer caused serious birth defects. As a result, a great deal of effort has been spent on devising methods to synthesize compounds that are purely one stereoisomer.
The reason stereoisomers may have such dramatically different biological effects is because they have very different 3-dimensional conformations. In the context of structure-based drug design, it is well-known in the art that proteins are often enantioselective towards their binding partners. Binding affinity is strongest when two binding partners have complementary geometry. Thus, when designing molecules to interact with biological targets, stereoselectivity is often a major consideration. As researchers expand their exploration of the chemical structure space for potential drug candidates, chirality is increasingly becoming a focal point.
One group of potential drug candidates is the Glyxin family, which are small peptides that mimic the biological activity of the monoclonal antibody B6B21. Importantly, monoclonal antibody B6B21 was found to act as a partial agonist on the glycine site of the NMDA receptor and NMDA partial agonists are currently being pursued as drugs to protect against stroke-induced neuronal damages and to alleviate neuropathic pain. The NMDA receptor is also involved in many cognitive functions, such as learning, memory, depression, and schizophrenia. Among the Glyxins, Glyx-13, also known as rapastinel, is one of the most effective leads.
While Glyx-13 is a great drug candidate, it does have at least one problem—it has to be injected in order to be administered. This is because of the poor bioavailability and enzymatic degradation it undergoes in the body.
Therefore, there exists a need for novel methods to manipulate the chiral centers of molecules. Such methods may be quite useful for designing and optimizing drug candidates, including derivatives of Glyx-13 with improved or optimized pharmacological properties in conjunction with optimized biological activity.